Dynamic cellular states require a rapid, efficient mechanism of protein catabolism. Cancer cells are highly dependent on protein degradation due to continuous cell cycling, hypermutation, and chromosomal rearrangements (Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004; 4:349-360; incorporated herein by reference). The proteasome and the aggresome are the two principal cellular structures involved in intracellular protein catabolism. The biology of the proteasome is well-characterized in normal and neoplastic cells. Proteasome complexes reside in numerous locations throughout the cell such as the endoplasmic reticulum (ER), nucleus, and cytoplasm. The primary role of the proteasome is the targeted degradation of ubiquitinated proteins. The aggresome is a juxtanuclear complex of misfolded proteins, chaperones, and proteasome components, which expands in response to proteasome inhibition or protein stress associated with certain pathologic states (Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 2000; 10:524-530; incorporated herein by reference). There are no known treatments targeting these pathologic states.
Aberrant protein catabolism is a hallmark of cancer, and is implicated in the stabilization of oncogenic proteins and the degradation of tumor suppressors (Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004; 4:349-360; incorporated herein by reference). Thus, there is a need in the art for treatments for diseases that involve aberrant protein catabolism as well as screening methods to develop new therapeutics to treat the diseases (e.g., cancer) by targeting protein degradation pathways and components.